生物活性

• 靶点	Chk1 IC50:7nM

• 描述Chk1 (Checkpoint kinase 1), an important serine/threonine kinase, is responding to DNA damage and stall DNA replication. Chk1 plays a key role in maintaining the replication fork viability during exposure to DNA antimetabolites. Inhibition of Chk1 will lead to accumulation of double-strand DNA breaks and cell death in human tumor cell lines exposure to antimetabolite. LY2603618 (Rabusertib) is a selective inhibitor of Chk1 with IC50 value of 7nM (measured by protein kinase assays). Treatment with 14-3300nM LY2603618 for 2h can dose-dependently decrease the level of phosphorylated Chk1 serine 296, an autophosphorylation reflecting Chk1 catalytic activity, in HeLa cells incubated with 100nM doxorubicin for 24h. Similar result can also be obtained in Calu6 Cells treated with 60nM gemcitabine. After treatment with LY2603618 1250 or 5000nM for 24h, increased level of p-H2A.X-S139 and p-H3-S10, the markers of DNA damage and mitotic, can be observed in HeLa cells. Meanwhile, a clear decrease in the G1 population and an increase in late S-phase cells, as well as cell arrest in an aberrant prometaphase state by LY2603618 can be observed. These indicated that inhibition of Chk1 by LY2603618 can abrogate the S-phase checkpoint. An increase in staining of the mitotic marker p-H3-Ser10 can be observed in HeLa cells treated for 24h with 100nM doxorubicin to cause a G2 arrest, then for 7h with serially diluted LY2603618. This indicated that LY2603618 can inactivate the G2/M DNA damage checkpoint^[1]. Combining 200mg/kg of LY2603618 with 160mg/kg of gemcitabine increased the tumor growth delay compared with gemcitabine alone in Calu-6 and HT-29 xenograft tumor models^[2]. Up to now, phase 2 studies of LY2603618 treatment for non small cell lung cancer and pancreatic neoplasms have been completed (see https://www.clinicaltrials.gov/).
• 作用机制LY2603618 bound in the ATP binding site of Chk1.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A549	~10 μM	Function assay	-	induces cell cycle arrest	24928205
  A549	~20 μM	Function assay	-	activates DNA damage sensor kinases	24928205
  A549	~20 μM	Apoptosis assay	-	induces apoptosis	24928205

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• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00415636	Cancer	Phase 1	Completed	-	United States, Arizona ... more >> For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Scottsdale, Arizona, United States, 85258 Collapse <<
  NCT00988858	Non Small Cell Lung Cancer	Phase 2	Completed	-	United States, Arizona ... more >> For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Tucson, Arizona, United States, 85704 United States, Colorado For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Denver, Colorado, United States, 80218 United States, Florida For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Tampa, Florida, United States, 33612 United States, Ohio For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Kettering, Ohio, United States, 45409 United States, Oregon For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Portland, Oregon, United States, 97213 United States, Texas For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Dallas, Texas, United States, 75201 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. The Woodlands, Texas, United States, 77380 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Tyler, Texas, United States, 75702 United States, Washington For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Yakima, Washington, United States, 98902 Italy For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Orbassano, Italy, 10043 Korea, Republic of For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Seoul, Korea, Republic of, 138-736 Taiwan For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Taichung, Taiwan, 407 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Tainan, Taiwan, 70403 Collapse <<
  NCT00988858	-	-	Completed	-	-

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• 参考文献

• [1] King C, Diaz H, et al. Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2014 Apr;32(2):213-26.

  [2] Barnard D, Diaz HB, et al. LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models. Invest New Drugs. 2016 Feb;34(1):49-60.